Regulation of Thyroid Function by Retinol Saturase

甲状腺激素是生长、细胞分化和能量平衡的主要调节者。这些激素在甲状腺的滤泡上皮细胞中合成，并分泌到血液中。一旦摄取到组织中，局部表达的脱碘酶就会以细胞类型特有的方式微调甲状腺激素的作用。我们发现，视黄醇饱和酶(RetSat)，一种最初被发现能将视黄醇还原为13，14-二氢视黄醇的NAD(P)H或FADH依赖的氧化还原酶，也可以催化其他反应，在小鼠和人类甲状腺中都有强烈的表达。此外，小鼠甲状腺中RetSat的表达被碘喂养改变，碘喂养是一种已知的甲状腺功能调节因子。为了分析RetSat在甲状腺中的功能，我们建立了一个新的遗传小鼠模型，该模型特异性地删除了甲状腺细胞中的RetSat。从这些小鼠身上获得的初步数据表明，RetSat与甲状腺激素的合成有关。因此，这项建议旨在研究潜在的机制，表征表型后果，并阐明RetSat在甲状腺功能低下和甲亢状态中的作用。解决这些问题将破译RetSat在甲状腺中的功能，并可能确定治疗甲状腺功能障碍和相关代谢病理的新的药理靶点。

Thyroid hormones are major regulators of growth, cell differentiation, and energy homeostasis. These hormones are synthesized in follicular epithelial cells of the thyroid gland and secreted into the blood. Upon the uptake into tissues, locally expressed deiodinases then fine-tune thyroid hormone action in a cell type-specific manner. We found that the enzyme Retinol Saturase (RetSat), a NAD(P)H or FADH-dependent oxidoreductase initially shown to reduce retinol to 13,14-dihydroretinol that may also catalyze other reactions, is strongly expressed in murine and human thyroid gland. Moreover, RetSat expression in the murine thyroid was altered by iodide feeding, a known modulator of thyroid function. To dissect the function of RetSat in the thyroid, we generated a new genetic mouse model that deletes RetSat specifically in thyrocytes. Preliminary data gained from these mice implicate RetSat in the synthesis of thyroid hormones. Hence, this proposal aims at investigating the underlying mechanisms, characterize the phenotypical consequences, and elucidate RetSat’s role in hypo-and hyperthyroid states. Addressing these question will decipher the function of RetSat in the thyroid gland and may identify a novel pharmacologic target to treat thyroid dysfunction and related metabolic pathologies.